Investigation of the H-bond-mediated aglycone delivery reaction in application to the synthesis of β-glucosides

Article abstract of DOI:10.1016/j.carres.2018.09.003

In an attempt to refine the H-bond-mediated Aglycone Delivery (HAD) glycosylation reaction reported herein is the synthesis of β-glucosides using an ethylthio glucoside donor equipped with the remote 6-O-picoloyl substituent. Upon examining various alipha

Full text of DOI:10.1016/j.carres.2018.09.003

Accepted Manuscript
Investigation of the H-bond-mediated aglycone delivery reaction in application to the
synthesis of β-glucosides
Michael P. Mannino, Jagodige P. Yasomanee, Alexei V. Demchenko
PII:
S0008-6215(18)30489-0
10.1016/j.carres.2018.09.003
CAR 7606
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 23 August 2018
Revised Date: 10 September 2018
Accepted Date: 10 September 2018
Please cite this article as: M.P. Mannino, J.P. Yasomanee, A.V. Demchenko, Investigation of the H-
bond-mediated aglycone delivery reaction in application to the synthesis of β-glucosides, Carbohydrate
Research (2018), doi: https://doi.org/10.1016/j.carres.2018.09.003.
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ACCEPTED MANUSCRIPT
Investigation of the H-bond-mediated aglycone delivery reaction in application to the
synthesis of β-glucosides
Michael P. Mannino, Jagodige P. Yasomanee, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis
One University Boulevard, St. Louis, MO 63121, USA
Fax: (+) 1-314-516-5342; e-mail: demchenkoa@umsl.edu
Abstract
In an attempt to refine the H-bond-mediated Aglycone Delivery (HAD)
glycosylation reaction reported herein is the synthesis of β-glucosides using an
ethylthio glucoside donor equipped with the remote 6-O-picoloyl substituent.
Upon examining various aliphatic, aromatic, and carbohydrate acceptors, it was
determined that both electronic and steric factors may greatly affect the
stereoselectivity of the HAD reaction with this donor.
Keywords: synthesis, stereoselectivity, glycosylation, oligosaccharides
Introduction
The chemical synthesis of glycans still faces many challenges and the biggest and most common
problem is chemical glycosylation, the reaction of joining saccharide units via O-glycosidic
1
-3
linkages. Due to the inherited mechanistic nature of this reaction, stereocontrol is often
4
,5
difficult to achieve. This results in the formation of undesired diastereomers, lowering yields
and complicating purification. There are various conditions and methods currently used to
6
,7
control stereoselectivity. Among these is the hydrogen-bond-mediated aglycone delivery
8
(
HAD) method. First reported in 2012, the HAD method employs a glycosyl donor
functionalized with a picoloyl (Pico) or similar moiety, a hydrogen bond accepting protecting
group. This picoloyl group forms a hydrogen bond with the free hydroxyl of the glycosyl
acceptor, forming an H-bonded donor-acceptor complex (Scheme 1). After addition of the
promoter, the donor is activated without disrupting the H-bonded complex, and the acceptor is
“delivered” to the anomeric position of the donor resulting in a facially preferential glycosidic
bond formation that is syn-selective with respect to the picoloyl protecting group.
8
The HAD reaction has successfully been applied to α-glucosylation using 4-O-Pico donor and
9
its utility was demonstrated by the synthesis of linear and branched α-glucans. Also
mannosylation with the use of either 3- or 6-O-Pico donors proceeded with high β-

ACCEPTED MANUSCRIPT
1
0
stereoselectivity, which was demonstrated by the sinthesis of a β-linked mannan at room
1
0
temperature. Further expansion of the HAD led to the development of new activation
1
1
12,13
14,15
conditions, protecting groups,
and glycosyl donors with switchable stereoselectivity.
-picoloyl-2-deoxy glycosyl donors to stereoselective
synthesis of β-glycosides. Yang and co-workers investigated the synthesis of β-D- and
Mong and co-workers applied 6-
O
16
12
17
18
β-L-arabinofuranosides, whereas De Meo and Tsai investigated the effect of picoloyl
substituents on sialylations.
Scheme 1. Mechanistic depiction of the HAD glycosylation method.
1
9
β-Glucosidic bonds are common glycosidic linkages that are often present in natural products
and various microbial, plant, and fungal glycan sequences.
2
0,21
Chemically, β-glucosides are
typically formed with high stereoselectivity from glycosyl donors functionalized with an acyl
protecting group at the C-2 position capable of the neighboring group participation. Upon
activation, these donors form the bicyclic acyloxonium ion intermediate that hinders the
2
2
nucleophilic attack from the bottom face of the ring. Despite this method’s popularity it is
2
3
prone to byproduct formation, such as an 1,2-O-orthoester, and regioselective selective
2
4
functionalization of the C-2 position can complicate the synthesis of glycosyl donors. In
contrast, the HAD method has been shown to form β-glucosides utilizing donors functionalized
at the primary C-6 position, offering enhanced synthetic flexibility. However, the preliminary
8
attempts were limited to glycosylation of primary hydroxyl of glucosyl acceptor. To broaden the
scope of the HAD-assisted synthesis of β-linked glucosides and disaccharides reported herein is
the investigation of thioglucoside donor 1. Compound 1 equipped with the 6-O-picoloyl
protecting group has already been shown to perform HAD glycosylations with β-
8
stereoselectively, and its synthesis is known.

ACCEPTED MANUSCRIPT
Results and Discussion
Previous glycosylations were performed in the presence of dimethyl(thiomethyl)sulfonium
triflate (DMTST) and molecular sieves (4 Å) in 1,2-dichloroethane (1,2-DCE) both under regular
(50 mM) and low (5 mM) concentration of donor 1. DMTST was added at -30 °C, and the
reaction mixture was then allowed to warm to room temperature. Thus, under these reaction
2
5,26
conditions that became standard for the HAD reactions, glycosylation of acceptor 2
donor 1 proceeded smoothly and β-stereoselectively affording disaccharide 3 in 78-90% yield
entry 1, Table 1). This result was practically the same as that previously reported for this donor-
with
(
8
acceptor combination. To expand upon these findings, the glycosylation of other common
carbohydrate acceptors with donor 1 were examined and the key findings are summarized in
Table 1. The primary acceptor 4 afforded the corresponding disaccharide 5 with respectable
yields of 81-91% and complete stereoselectivity (entry 2). Very unexpectedly, the β-
2
7
stereoselectivity was dramatically decreased when benzoylated primary acceptor 6 was
glycosylated. The reaction was still fairly swift (1.5 h), and respectable yields for the synthesis of
disaccharide 7 (82-92%) have been achieved, but the stereoselectivity was fairly low (α/β =
1
/2.7-2.9, entry 3) in comparison to the results obtained with other primary acceptors (vide
supra). This last result made us believe that the efficacy of the HAD reaction with donor 1 can
be greatly dependent on the electronic properties of the glycosyl acceptor. Thus, with the electro-
withdrawing substituents in acceptor 7, the electron density on the hydroxyl group is decreased
in comparison to that of alkylated counterparts. As a result, the hydrogen-bond-donating
properties of such electron-poor glycosyl acceptor are reduced and the picoloyl-assisted H-bond-
mediated aglycone delivery becomes less prevalent reaction pathway.
Table 1. Glycosylation of primary and secondary glycosyl acceptors with donor 1
Entry Acceptor (ROH) Conc. of 1, time
Product
yield (α/β ratio)
PicoO
O
O
BnO
BnO
5
mM, 2 h
78% (β-only)
90% (β-only)
1
2
3
O
BnO
BnO
BnO
5
0 mM, 3 h
2
BnO
3
OMe
5
mM, 1.5 h
91% (β-only)
81% (β-only)
5
5
0 mM, 1.5 h
4
6
5
mM, 1.5 h
82% (1/2.7)
92% (1/2.9)
0 mM, 1.5 h

ACCEPTED MANUSCRIPT
5
mM, 24 h
42% (1/1.3)
48% (1/2.6)
4
5
0 mM, 24 h
8
5
mM, 24 h
49% (1/2.5)
43% (1/1.0)
5
6
7
5
5
5
0 mM, 24 h
1
0
2
4
5
mM, 24 h
37% (1/2.5)
31% (1/3.5)
0 mM, 24 h
1
1
5
mM, 24 h
38% (1/4.3)
31% (1/2.5)
0 mM, 24 h
The less reactive, more sterically hindered secondary acceptors also proved to be problematic for
the HAD reaction with donor 1. Poor yields and stereoselectivities, as well as long reaction
2
8
29
30
times, were observed for acceptors 8, 10, and 12 (entries 4-6). An improvement in
3
1
stereoselectivity was seen with the methylated secondary acceptor 14 (entry 7). The reactivity
of acceptor 14, however, was still fairly low leading to long reaction times and low yields. This
last result made us believe that the stereoselectivity of the HAD reaction with donor 1 can be
also dependent on the steric properties of the glycosyl acceptor. Thus, with the bulky benzyl
substituents are present in the glycosyl acceptor, the accessibility of the secondary hydroxyl to
form strong H-bonding with bulky picoloyl moiety of the donor is low in comparison to that of
less hindered methylated (or primary) counterparts. As a result, the H-bond-donating properties
of such hindered glycosyl acceptors are reduced and the picoloyl-assisted delivery becomes a
less prevalent stereodirecting pathway. In an attempt to improve results with secondary
acceptors, various reaction conditions were investigated in the glycosylation of donor 1 and
secondary acceptor 10. Slightly improved selectivity was observed upon switching to the
stronger promoter system of NIS/TfOH. The extended experimental data can be found in the
supporting information.
These results were puzzling to us because previously investigated 4-O-Pico donor provided
excellent syn-stereoselectivity for the synthesis of α-glucosides, which was practically
8
independent on the nature of the glycosyl acceptor. On the other hand, the previously
investigated 6-O-Pico mannosyl donor provided high syn-stereoselectivity for the synthesis of β-
8
,10
mannosides.
To develop a convenient tool-kit for studying this controversial reaction, we
turned our attention to glycosylation of small molecule acceptors that could serve a simplified
albeit more easily tunable platform for studying possible electronic and steric effects on the
outcome of the HAD reaction. The key results of this study performed under low concentration
conditions (5 mM of glycosyl donor 1) are summarized in Table 2. Thus, all initially chosen
primary aliphatic acceptors exhibited complete β-selectivity and the corresponding glycosides
1
6-19 we obtained in moderate-to-excellent yields (56-86%, entries 1-4). However, the
stereoselectivity was diminished when 2,2,2-trichloroethanol was employed as the glycosyl
acceptor. Thus, glycosylation of this more electron poor trichloro-substituted acceptor led to the

ACCEPTED MANUSCRIPT
formation of glycoside 20 in 77% with decreased selectivity α/β = 1/11.4 (entry 5) in comparison
to the complete β-selectivity obtained with non-substituted ethanol (entry 1).
Table 2. Glycosylation of small molecule acceptors to study the effect of steric and electronic
factors on the HAD reaction
Product
yield, α/β ratio)
Entry
1
Acceptor
EtOH
Time
0.5 h
(
1
6 (86%, β-only)
2
3
4
5
0.5 h
0.5 h
0.5 h
0.5 h
1
1
1
7 (73%, β-only)
8 (56%, β-only)
9 (57%, β-only)
3 2
Cl CCH OH
2
0 (77%, 1/11.4)
6
7
1.5 h
1.5 h
21 (77%, 1/3.6)
2
2 (63%, 1/2.6)
3 (78%, 1/1.1)
4 (56%, 1/4.0)
8
9
1.5 h
1.5 h
2
2

ACCEPTED MANUSCRIPT
1
1
0
1
1.5 h
2
2
2
5 (81%, 1/4.7)
1.5 h
1.5 h
6 (63%, 1/5.5)
1
2
7 (52%, 1/1.2)
To investigate the role of steric factors on the stereoselectivity of these reactions, we chose a
number of secondary and tertiary small molecule acceptors. The results of these glycosylations
are summarized in entries 6-9 (Table 2). Thus, glycosides 21-24 were obtained in 56-78% yields,
but the stereoselectivity was even lower than that obtained with 2,2,2-trichloroethanol (α/β =
1
/1.0-4.0). To further investigate the effect of electronic factors on the stereoselectivity we
chose a series of substituted phenol acceptors. Although stereoselectivity of glycosylation has
3
2
been a well-documented problem with phenol acceptors, their scalable electronic properties
made them attractive targets for our study. The results of these glycosylations are summarized in
entries 10-12. Thus, glycosides 25-27 were obtained in 52-81% yields, but the stereoselectivity
was modest (α/β = 1/1.2-5.5). Nevertheless, these results reveal a clear correlation between the
electronics quantified by relative acidity of the aromatic acceptors and the stereoselectivity of
their glycosylation. Specifically, as compared to unsubstituted phenol (pK = 10) that afforded
a
3
3
glycoside 25 (α/β = 1/4.7, entry 10), a slightly less acidic p-methoxyphenol (pK = 10.2)
a
showed a modest enhancement of stereoselectivity for the formation of glycoside 26 (α/β = 1/5.5,
3
3
entry 11). Conversely, glycosylation of a much more acidic p-nitrophenol (pK = 7.2) led to the
a
formation of glycoside 27 with practically entire loss of stereoselectivity (α/β = 1/1.2, entry 12).
In our opinion, this series of results clearly indicate the effect of the glycosyl acceptor on the
stereoselectivity outcome of the HAD reaction
Conclusions
The glycosylations of the HAD-capable glycosyl donor 1 with various glycosyl acceptors were
investigated. Primary acceptors, both carbohydrate and aliphatic alcohols afforded the
glycosylation products with complete β-selectivity. Secondary acceptors and some primary
acceptors with the reduced electron density of the hydroxyl group exhibited reduced
stereoselectivity. Additionally, secondary carbohydrate acceptors had long reaction times and, in
a number of cases, modest yields. Relieving some of the steric crowding in secondary acceptors,
such as that noted with the methylated acceptor 14, led to a slightly improved stereoselectivity.
The effect of electronic properties of glycosyl acceptors were further investigated by

ACCEPTED MANUSCRIPT
glycosylation of a series of phenolic acceptors. These reactions revealed a possible preliminary
correlation between the electronics or acidity of the hydroxyl to the stereoselectivity observed.
These findings are in agreement with the theory that hydrogen bonding is responsible for the
observed selectivity in the HAD reactions. It has been well documented that both acidity and
sterics of hydrogen-bond donors, the glycosyl acceptors in this case, can have a great influence
3
4
on the hydrogen-bond strength. Interestingly, these factors do not seem important when
employing 4-O-picoloyl donors that previously gave completely α-selective HAD-glycosylations
8
with both primary and secondary acceptors.
EXPERIMENTAL PART
General. Column chromatography was performed on silica gel 60 (70-230 mesh), reactions
were monitored by TLC on Kieselgel 60 F254. The compounds were detected by examination
under UV light and by charring with 10% sulfuric acid in methanol. Solvents were removed
2 2 2 2 2
under reduced pressure at <40 °C. CH Cl and ClCH CH Cl (1,2-DCE) were distilled from CaH
directly prior to application. Molecular sieves (4 Å) used for reactions were crushed and
activated in vacuo at 390 °C for an initial 8 h and then for 2-3 h at 390 °C directly prior to
application. Optical rotations were measured at ‘Jasco P-2000’ polarimeter. Unless noted
1
13
otherwise, H NMR spectra were recorded in CDCl at 300 or 600 MHz, C NMR spectra were
3
recorded in CDCl at 75 MHz.
3
The synthesis of disaccharides
General procedure. Glycosyl donor 1 (0.05 mmol) and a glycosyl acceptor (0.038 mmol) were
dried in high vacuum for 1 h at rt. Molecular sieves (4 Å, 60 mg or 150 mg for 50 mM or 5 mM
reaction, respectively) and freshly distilled 1,2-dichloroethane (1.0 mL or 10.0 mL for 50 mM or
5
mM reaction, respectively) were added and the resulting mixture was stirred under argon for 1
h at rt. The mixture was cooled to -30 °C and DMTST (0.1 mmol) was added. The external
cooling was removed, and the reaction mixture was allowed to warm up to rt gradually. Upon
completion (see the time listed in Table 1), the solid was filtered off through a pad of Celite and
rinsed successively with dichloromethane. The combined filtrate (~30 mL) was washed with sat.
aq. NaHCO (10 mL) and water (2 × 10 mL). The organic phase was separated, dried with
3
magnesium sulfate, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate – hexanes gradient elution). Diastereomeric ratios
1
were determined by comparison of the integral intensities of relevant signals in H NMR spectra.
Methyl O-(2,3,4-tri-O-benzyl-6-O-picoloyl-β-
-glucopyranoside (3) was obtained as a clear syrup from glycosyl donor 1 and acceptor 2
in 90% (β-only, 50 mM) and 78% (β-only, 5 mM) yield. The analytical data of the title
D-glucopyranosyl)-(1→6)-2,3,4-tri-O-benzyl-α-
8
25,26
D
8
,35
compound were essentially the same as previously reported.
O-(2,3,4-Tri-O-benzyl-6-O-picoloyl-β-
isopropylidene-α- -galactopyranose (5) was obtained as a yellow oil from glycosyl donor 1
and commercial acceptor 4 in 91% (β-only, 50 mM) and 70% (β-only, 5 mM) yield. Analytical
D
-glucopyranosyl)-(1→6)-1,2:3,4-di-O-
D

ACCEPTED MANUSCRIPT
2
2
1
data for 5: R
.30, 1.30, 1.42, 1.47 (4 s, 12H, 4 x CH
H-3’, 4’, 5’, 6a), 4.06-4.10 (m, 2H, H-5, 6b), 4.19 (dd, 1H, J3,4 = 8.0 Hz, H-3), 4.30 (dd, 1H, J2,3
4.8 Hz, H-2), 4.52 (d, 1H, J1’,2’ = 7.8 Hz, H-1’), 4.53-4.63 (m, 4H, H-4, 6a’, 6b’, ½ CH Ph),
f
= 0.44 (ethyl acetate/toluene, 2/3, v/v); [α]
D
3
-9.7 (c = 0.98, CHCl ); H NMR: δ,
1
3
), 3.50 (dd, 1H, J2’,3’ = 8.3 Hz, H-2’), 3.64-3.75 (m, 4H,
=
2
2
2
2
4
.73 (d, 1H, J = 11.2 Hz, ½ CH Ph), 4.80 (d, 1H, J = 10.8 Hz, ½ CH Ph), 4.88 (d, 1H, J = 10.8
2
2
2
2
Hz, ½ CH Ph), 4.99 (d, 1H, J = 10.8 Hz, ½ CH Ph), 5.06 (d, 1H, J = 11.2 Hz, ½ CH Ph), 5.55
2
2
2
(
d, 1H, J1,2 = 5.0 Hz, H-1), 7.21-7.43 (m, 15H, aromatic), 7.45-7.48 (m, 1H, Pico), 7.81 (dd, 1H,
1
3
J = 7.6 Hz, Pico), 8.04 (d, 1H, J = 7.8 Hz, Pico), 8.76 (d, 1H, J = 4.8 Hz) ppm; C NMR: δ,
2
9
1
7
4.4, 25.0, 26.0 (×2), 64.4, 67.4, 70.0, 70.4, 70.7, 71.4, 72.8, 74.4, 75.0, 75.8, 77.5, 81.6, 84.6,
6.3, 104.5, 108.5, 109.3, 125.3, 126.6, 127.5, 127.7, 127.9, 128.0, 128.2, 128.4, 128.6, 136.9,
+
37.7, 138.4, 138.6, 147.8, 150.0, 164.6 ppm; HR-FAB MS [M+H] calcd for C H NO
4
5
52
12
98.3489, found 787.3538.
Methyl
O-(2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D
-glucopyranosyl)-(1→6)-2,3,4-tri-O-
benzoyl-α-
D-glucopyranoside (7) was obtained as a clear syrup from glycosyl donor 1 and
2
7
acceptor 6 in 92% (α/β = 1/2.9, 50 mM) and 82% (α/β = 1/2.7, 5 mM) yield. Analytical data for
1
7
: R
f
= 0.63 (ethyl acetate/toluene, 2/3, v/v); selected H NMR data for α-7: δ, 3.53 (s, 3H,
1
OCH ) ppm; selected H NMR data for β-7: δ, 3.42 (s, 3H, OCH ), 3.88 (dd, 1H, J = 7.2 Hz,
3
3
5,6a
2
J6a,6b = 11.1 Hz, H-6a), 4.38-4.43 (m, 1H, H-5), 4.77 (d, 1H, J = 10.8 Hz, ½ CH Ph), 4.85 (d,
2
2
2
2
1
H, J = 10.8 Hz, ½ CH Ph), 4.94 (d, 1H, J = 10.8 Hz, ½ CH Ph), 5.02 (d, 1H, J = 10.8 Hz, ½
2
2
2
CH Ph), 5.16 (d, 1H, J = 10.8 Hz, ½ CH Ph), 5.52 (dd, 1H, J = 9.8 Hz, H-4), 6.20 (dd, 1H,
2
2
4,5
1
3
J3,4 = 9.5 Hz, H-3), 8.80 (d, 1H, J = 4.6 Hz, Pico) ppm; selected C NMR data for β-7: δ, 55.6,
4.3, 68.8, 69.8, 70.4, 72.0, 72.9, 74.9, 75.0, 75.9, 77.4, 82.2, 84.5, 96.8, 104.0 ppm; HR-FAB
6
+
MS [M+Na] calcd for C H NNaO 1066.3626, found 1066.3641.
6
1
57
15
Methyl O-(2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-
α- -glucopyranoside (9) was obtained as a clear syrup from glycosyl donor 1 and acceptor 8
in 48% (α/β = 1/1.3, 50 mM) and 42% (α/β = 1/2.6, 5 mM) yield. Analytical data for 9: R = 0.57
ethyl acetate/toluene, 2/3, v/v); selected H NMR data for α-9: δ, 3.34 (s, 3H, OMe), 7.98 (dd,
D
-glucopyranosyl)-(1→2)-3,4,6-tri-O-benzyl-
2
8
D
f
1
(
1
1
1
H, J = 7.8 Hz, Pico) ppm; selected H NMR data for the β-9: δ, 3.45 (s, 3H, OMe), 3.87 (dd,
1
3
H, J2,3 = 9.9 Hz, H-2), 8.03 (d, 1H, J = 7.8 Hz, Pico) ppm; selected C NMR data for the
+
anomeric region of α/β-9: δ, 93.9, 99.3, 99.5, 104.1 ppm; HR-FAB MS [M+H] calcd for
C H NO Na 1024.4248, found 1024.4246.
61
63
12
Methyl O-(2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-
D-glucopyranosyl)-(1→3)-2,4,6-tri-O-benzyl-
α- -glucopyranoside (11) was obtained as a clear syrup from glycosyl donor 1 and acceptor
D
2
9
1
0 in 43% (α/β = 1/1.0, 50 mM) and 49% (α/β = 1/2.5, 5 mM) yield. Analytical data for 11: R
f
1
=
0.24 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data for α-11: δ, 3.31 (s, 3H, OCH ),
3
4
.12 (dd, 1H, J3’,4’ = 9.1 Hz, H-3’), 5.57 (d, 1H, J1’2’ = 3.1 Hz, H-1’), 7.78 (dd, 1H, J = 7.8 Hz,
1
Pico), 8.05 (d, 1H, J = 7.8 Hz, Pico), 8.74 (d, 1H, J = 4.8 Hz, Pico) ppm; selected H NMR data
for β-11: δ, 3.29 (s, 3H, OCH ), 7.59 (dd, 1H, J = 7.8 Hz, Pico), 7.86 (d, 1H, J = 7.8 Hz, Pico),
3
1
3
8
9
1
.70 (d, 1H, J = 3.9 Hz, Pico) ppm; selected C NMR data for the anomeric region of α/β-11: δ,
+
7.1, 97.3, 97.7, 102.7 ppm; HR-FAB MS [M+Na] calcd for C61
024.4246.
H63NNaO12 1024.4248, found

ACCEPTED MANUSCRIPT
Methyl O-(2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-
D-glucopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-
α-
D
-glucopyranoside (13) was obtained as a clear syrup from glycosyl donor 1 and acceptor
3
0
1
2 in 31% (α/β = 1/3.5, 50 mM) and 37% (α/β = 1/2.5, 5 mM) yield. Analytical data for 13: R =
f
1
0
.30 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data for α-13: δ, 3.38 (s, 3H, OCH ), 5.57
3
(
d, 1H, J1 = 3.7 Hz, H-1’), 7.75 (dd, 1H, J = 7.8 Hz, Pico), 7.98 (d, 1H, J = 7.8 Hz, Pico) ppm;
’,2’
1
2
selected H NMR data for β-13: δ, 3.36 (s, 3H, OCH ), 5.05 (d, 1H, J = 11.3 Hz, ½ CH Ph),
7
the anomeric region of α/β-13: δ, 96.5, 97.9, 98.5, 102.7 ppm; HR-FAB MS [M+Na] calcd for
3
2
1
3
.60 (dd, 1H, J = 7.6 Hz, Pico), 7.85 (d, 1H, J = 7.8 Hz, Pico) ppm; selected C NMR data for
+
C H NNaO 1024.4248, found 1024.4246.
61
63
12
Methyl O-(2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-
D
-glucopyranosyl)-(1→4)-2,3,6-tri-O-methyl-
α- -glucopyranoside (15) was obtained as a clear syrup from glycosyl donor 1 and acceptor
D
3
1
1
4 in 31% (α/β = 1/2.5, 50 mM) and 38% (α/β = 1/4.3, 5 mM) yield. Analytical data for α-15:
2
2
1
R
3
OCH
=
f
= 0.38 (ethyl acetate/dichloromethane, 1/1, v/v); [α]
D
93.4 (c = 0.88, CHCl
), 3.47-3.50 (m, 7H, H-6b, 2 ×
), 3.62 (dd, 1H, J2’,3’ = 9.8 Hz, H-2’), 3.69 (dd, 1H, J4’,5’ = 9.3 Hz, H-4’), 3.74 (dd, 1H, J3,4
9.1 Hz, H-3), 3.98-4.01 (m, 2H, H-5, 6a), 3.90-3.92 (m, 1H, H-5’), 3.95 (dd, 1H, J4,5 = 9.4 Hz,
3
); H NMR: δ,
.27 (dd, 1H, J2,3 = 9.5 Hz, H-2), 3.33, 3.40 (2 s, 6H, 2 × OCH
3
3
H-4), 4.00 (dd, 1H, J3’,4’ = 9.2 Hz, H-3’), 4.53 (dd, 1H, J
= 11.8 Hz, H-6a’), 4.62-4.64 (m,
6a’6b’
2
2
2
H, H-6a’, ½ CH Ph), 4.74 (d, 1H, J = 11.7 Hz, ½ CH Ph), 4.83 (d, 1H, J = 11.7 Hz, ½
2
2
2
2
CH Ph), 4.85 (d, 1H, J = 3.5 Hz, H-1), 4.89 (d, 1H, J = 11.1 Hz, ½ CH Ph), 4.97 (d, 1H, J =
2
1,2
2
1
0.5 Hz, ½ CH Ph), 5.70 (d, 1H, J1’,2’ = 3.5 Hz, H-1’), 7.17-7.37 (m, 15H, aromatic), 7.44-7.45
2
(
m, 1H, Pico), 7.79 (dd, 1H, J = 7.7 Hz, Pico), 8.01 (d, 1H, J = 7.8 Hz, Pico), 8.75 (d, 1H, J = 4.6
1
3
Hz, Pico) ppm; C NMR: δ, 55.1, 58.7, 59.0, 60.1, 64.0, 69.0, 69.2, 70.6, 70.8, 73.2, 75.0, 75.9,
7
1
7.1, 79.9, 82.0, 82.1, 83.4, 95.9, 97.1, 125.2, 126.8, 127.8 (× 2), 127.9, 128.0 (× 4), 128.1 (× 2),
28.4 (× 2), 128.5 (× 3), 136.8 (× 2), 137.8, 138.4, 147.7, 150.1 (× 2), 164.6 ppm. Analytical
2
2
data for β-15: R = 0.15 (ethyl acetate/dichloromethane, 1/1, v/v); [α] 57.6 (c = 0.74, CHCl3);
f
D
1
H NMR: δ, 3.09 (dd, 1H, J2,3 = 9.6 Hz, H-2), 3.26-3.37 (2 s, 6H, 2 × OCH ), 3.41-3.47 (m, 10H,
3
H-2’, 3, 5, 6a, 2 × OCH
3
), 3.54-3.56 (m, 1H, H-6b), 3.63-3.73 (m, 4H, H-3’, 4, 4’, 5’), 4.45 (d,
1
1
1
7
=
H, J1’,2’ = 7.8 Hz, H-1’), 4.61-4.63 (m, 3H, H-6a’, 6b’, ½ CH Ph), 4.76 (d, 1H, J1,2 = 3.6 Hz, H-
2
2
2
2
), 4.80 (d, 1H, J = 11.4 Hz, ½ CH
2
Ph), 4.83 (d, 1H, J = 10.9 Hz, ½ CH
Ph), 4.94 (d, 1H, J = 10.7 Hz, ½ CH Ph), 7.19-7.33 (m, 15H, aromatics), 7.44-
.45 (m, 1H, Pico), 7.78 (dd, 1H, J = 7.7 Hz, Pico), 8.03 (d, 1H, J = 7.9 Hz, Pico), 8.75 (d, 1H, J
2
Ph), 4.86 (d, 2H, J =
2
1.1 Hz, ½ CH
2
2
1
3
4.5 Hz, Pico) ppm; C NMR: δ, 29.7, 55.3, 58.9, 59.3, 60.2, 64.1, 69.6, 70.0, 72.6, 75.0, 75.1,
7
1
1
5.9, 77.4, 77.7, 80.6, 81.1, 82.6, 85.2, 97.7, 102.9, 125.2, 126.8, 127.6, 127.7 (× 2), 127.8 (× 3),
27.9, 128.1 (× 2), 128.3 (× 2), 128.4 (× 2), 128.5 (× 2), 136.8, 137.6, 138.2, 147.8, 150.0 (× 2),
64.5 ppm; HR-FAB MS [M+H]+ calcd for C H NNaO 796.3308, found 796.3341.
4
3
51
12
The synthesis of glycosides
General procedure. Glycosyl donor 1 (0.05 mmol) was dried in high vacuum for 1 h at rt.
Molecular sieves (4 Å, 150 mg), freshly distilled 1,2-dichloroethane (10.0 mL), and an aliphatic
or aromatic glycosyl acceptor (0.038 mmol) were added and the resulting mixture was stirred
under argon for 1 h at rt. The mixture was cooled to -30 °C and DMTST (0.1 mmol) was added.
The external cooling was removed, and the reaction mixture was allowed to warm up to rt
gradually. Upon completion (see the time listed in Table 2), the solid was filtered off through a

ACCEPTED MANUSCRIPT
pad of Celite and rinsed successively with dichloromethane. The combined filtrate (~30 mL) was
washed with sat. aq. NaHCO (10 mL) and water (2 × 10 mL). The organic phase was separated,
3
dried with magnesium sulfate, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate – hexanes gradient elution). Diastereomeric ratios
1
were determined by comparison of the integral intensities of relevant signals in H NMR spectra.
Ethyl 2,3,4-tri-O-benzyl-6-O-picoloyl-β-D-glucopyranoside (16) obtained as a clear syrup
from glycosyl donor 1 and freshly distilled ethanol in 86% yield (β-only). Analytical data for 16:
2
D
2
1
R = 0.21 (ethyl acetate/hexane, 2/3, v/v); [α] 30.4 (c = 0.41, CHCl ); H NMR: δ, 1.18 (t, 3H,
f
3
OCH CH ), 3.51 (dd, 1H, J = 8.1 Hz, H-2), 3.51-3.67 (m, 4H, H-3, 4, 5, ½ CH CH ), 3.83-3.93
2
3
2,3
2
3
if this is symmetrical, needs just the middle ppm value (m, 1H, ½ CH CH ), 4.38 (d, 1H, J =
2
3
1,2
7
CH
.8 Hz, H-1), 4.49 (dd, 1H, J5 = 4.9 Hz, J6a,6b = 10.9 Hz, H-6a), 4.54-4.59 (m, 2H, H-6b, ½
,6a
2
2
2
Ph), 4.66 (d, 1H, J = 11.0 Hz, ½ CH
2
Ph), 4.73 (d, 1H, J = 10.9 Hz, ½ CH
2
Ph), 4.82 (d, 1H,
2
2
J = 10.9 Hz, ½ CH
2
Ph), 4.90 (d, 1H, J = 10.9 Hz, ½ CH
2
Ph), 7.14-7.30 (m, 15H, aromatic),
7
1
1
1
.37-7.42 (m, 1H, Pico), 7.74 (dd, 1H, J = 7.7 Hz, Pico), 7.98 (d, 1H, J = 7.8 Hz, Pico), 8.70 (d,
H, J = 4.0 Hz, Pico) ppm; C NMR: δ, 15.3, 64.5, 65.8, 72.8, 74.9, 75.1, 75.9, 77.6, 82.2, 84.7,
1
3
03.5, 125.2, 126.9, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5 (× 3), 136.9, 138.4,
+
50.0 ppm; HR-FAB MS [M+Na] calcd for C H NNaO 606.2468, found 606.2468.
3
5
37
7
4
-Azidobutyl 2,3,4-tri-O-benzyl-6-O-picoloyl-β-
D
-glucopyranoside (17) was obtained as a
3
6,37
colorless syrup from glycosyl donor 1 and 4-azido-1-butanol
in 73% yield (β-only).
2
2
Analytical data for 17: R = 0.69 (ethyl acetate/toluene, 2/3, v/v); [α] 30.1 (c = 0.39, CHCl3);
f
D
1
H NMR: δ, 1.62-1.71 (m, 4H, -CH CH -), 3.2-3.26 (m, 2H, -CH N ), 3.45 (dd, 1H, J = 8.7
2
2
2
3
2,3
Hz, H-2), 3.52-3.55 (m, 1H, ½ -OCH CH -), 3.62 (dd, 1H, J = 9.1 Hz, H-4), 3.66-3.70 (m, 1H,
2
2
4,5
H-5), 3.70 (dd, 1H, J3,4 = 8.9 Hz, H-3), 3.87-3.89 (m, 1H, ½ -OCH CH -), 4.41 (d, 1H, J = 7.8
2
2
1,2
2
Hz, H-1), 4.56 (dd, 1H, J5 = 5.2 Hz, J6a,6b = 11.9 Hz, H-6a), 4.62 (d, 2H, J = 11.1 Hz, H-6b, ½
CH Ph), 4.73 (d, 1H, J = 11.1 Hz, ½ CH Ph), 4.80 (d, 1H, J = 10.7 Hz, ½ CH Ph), 4.89 (d, 1H,
J = 10.9 Hz, ½ CH Ph), 4.91 (d, 1H, J = 11.1 Hz, ½ CH Ph), 4.95 (d, 1H, J = 10.7 Hz, ½
2 2
,6a
2
2
2
2
2
2
2
2
2
CH Ph), 7.22-7.36 (m, 15H, aromatic), 7.45-7.48 (m, 1H, Pico), 7.82 (dd, 1H, J = 7.7 Hz, Pico),
1
3
8
6
1
.04 (d, 1H, J = 7.7 Hz, Pico), 8.76 (d, 1H, J = 4.5 Hz, Pico) ppm; C NMR: δ, 25.6, 26.9, 51.1,
4.4, 69.2, 72.9, 74.9, 75.1, 75.9, 77.7, 82.2, 84.7, 103.5, 125.2, 126.9, 127.8 (× 2), 128.0 (× 5),
28.1 (× 2), 128.4 (× 3), 128.5 (× 6), 136.9, 137.6, 138.3, 147.7, 150.0 ppm; HR-FAB MS
[
M+Na]+ calcd for C H NNaO 675.2795, found 675.2798.
37 40 7
8
-Trityloxyoctyl 2,3,4-tri-O-benzyl-6-O-picoloyl-β-D-glucopyranoside (18) was obtained as a
3
8
yellow syrup from glycosyl donor 1 and 8-trityloxy-1-octanol in 56% yield (β-only). Analytical
data for 18: R = 0.56 (ethyl acetate/hexane, 2/3, v/v); [α] 26.2 (c = 0.42, CHCl ); H NMR: δ,
2
D
2
1
f
3
1
.19-1.32 (m, 8H, 4 x C-CH -C), 1.55-1.62 (m, 4H, 2 x C-CH -C), 3.00 (t, 2H, CH OTr), 3.47
2 2 2
(
dd, 1H, J2,3 = 8.7 Hz, H-2), 3.47-3.50 (m, 1H, ½ C-1-OCH -), 3.62 (dd, 1H, J = 9.4 Hz, H-4),
2 4,5
3
.67-3.70 (m, 1H, H-5), 3.70 (dd, 1H, J3,4 = 8.9 Hz, H-3), 3.85-3.89 (m, 1H, ½ C-1-OCH -), 4.42
2
2
(d, 1H, J1,2 = 7.8 Hz, H-1), 4.56 (dd, 1H, J5,6b = 5.1, J6a,6b = 11.8 Hz, H-6a), 4.61(d, 2H, J = 10.7
2
2
Hz, H-6b, ½ CH Ph), 4.71 (d, 1H, J = 10.9 Hz, ½ CH Ph), 4.80 (d, 1H, J = 10.9 Hz, ½ CH Ph),
4
2
2
2
2
2
2
.88 (d, 1H, J = 10.9 Hz, ½ CH
2 2
Ph), 4.94 (d, 1H, J = 10.9 Hz, ½ CH Ph), 4.95 (d, 1H, J = 10.8
Hz, ½ CH Ph), 7.19-7.43 (m, 31H, aromatic), 7.78 (dd, 1H, J = 7.7 Hz, Pico), 8.03 (d, 1H, J =
2
1
3
7
6
.8 Hz, Pico), 8.74 (d, 1H, J = 4.5 Hz, Pico) ppm; C NMR: δ, 26.1, 26.2, 29.3, 29.5, 29.7, 30.0,
3.6, 64.5, 70.3, 72.8, 74.8, 75.1, 75.9, 77.7, 82.2, 84.7, 103.6, 125.2, 126.8 (× 3), 126.9, 127.7

ACCEPTED MANUSCRIPT
(
1
× 8), 127.9, 128.0 (× 2), 128.1 (× 3), 128.4 (× 4), 128.5 (× 2), 128.7 (× 6), 136.9 (× 2), 137.7,
38.3, 144.5 (× 5), 147.8, 150.0 (× 2), 164.7 ppm; HR-FAB MS [M+Na] calcd for
+
C H NNaO 948.4452, found 948.4409.
60
63
8
Benzyl 2,3,4-tri-O-benzyl-6-O-picoloyl-β-D-glucopyranoside (19) was obtained as a colorless
syrup from glycosyl donor 1 and benzyl alcohol in 57% yield (β-only). Analytical data for 19: R
f
2
2
1
=
0.28 (ethyl acetate/hexane, 2/3, v/v); [α]D 8.3 (c = 0.99, CHCl ); H NMR: δ, 3.48 (dd, 1H,
3
J2,3 = 8.2 Hz, H-2), 3.58-3.67 (m, 3H, H-3, 4, 5), 4.47 (d, 1H, J1,2 = 7.7 Hz, H-1), 4.55-4.58 (m,
2
2
3
H, H-6a, 6b, ½ CH Ph), 4.65 (d, 1H, J = 11.0 Hz, ½ CH Ph), 4.72 (d, 1H, J = 10.7 Hz, ½
2
2
2
CH Ph), 4.83 (d, 1H, J = 11.2 Hz, ½ CH Ph), 4.85-4.91 (m, 3H, 1.5 × CH Ph), 7.18-7.26 (m,
2
2
2
1
5H, aromatic), 7.39-7.42 (m, 1H, Pico), 7.75 (dd, 1H, J = 7.4 Hz, Pico), 8.00 (d, 1H, J = 7.8 Hz,
1
3
Pico), 8.71 (d, 1H, J = 3.3 Hz, Pico) ppm; C NMR: δ, 64.4, 71.1, 72.9, 74.9, 75.0, 75.9, 77.6,
8
1
2.2, 84.7, 102.2, 125.2, 126.9, 127.7, 127.8, 127.9 (× 2), 128.0 (× 2), 128.1 (× 4), 128.2 (× 2),
28.4 (× 4), 128.5 (× 4), 136.9, 137.1, 137.6, 138.2, 138.3, 147.8, 150.1, 164.7 ppm; HR-FAB
+
MS [M+Na] calcd for C40
H
39NNaO
7
668.2625, found 668.2632.
2
,2,2-Trichloroethyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (20) was
obtained as a clear syrup from glycosyl donor 1 and 2,2,2-trichloroethanol in 77% yield (α/β =
1
1
/11.4). Analytical data for 20: R = 0.31 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data
f
2
for β-20: δ, 3.57-3.77 (m, 4H, H-2, 3, 4, 5), 4.17 (d, 1H, J = 11.9 Hz, ½ CH CCl ), 4.43 (d, 1H,
J = 11.9 Hz, ½ CH CCl ), 4.60-4.83 (m, 6H, H-1, 6a, 6b, 3 × ½ CH Ph,), 4.89 (d, 1H, J = 10.8
Hz, ½ CH Ph), 4.99 (d, 1H, J = 10.2 Hz, ½ CH Ph), 5.11 (d, 1H, J = 10.6 Hz, ½ CH Ph), 7.23-
2
3
2
2
2
3
2
2
2
2
2
2
7
=
.40 (m, 15H, aromatic), 7.47-7.51 (m, 1H, Pico), 7.84 (dd, 1H, J = 7.7 Hz, Pico), 8.04 (d, 1H, J
7.7 Hz, Pico), 8.77-8.79 (m, 1H, Pico) ppm; selected C NMR data for β-20: δ, 62.9, 63.7,
1
3
7
1
2.7,74.6, 74.7, 75.5, 76.8, 80.1, 81.3, 83.9, 95.9, 103.4, 124.8, 126.6, 127.4 (× 2), 127.5 (× 3),
27.6, 127.7 (× 2), 128.0 (× 8), 136.5, 137.0, 137.5, 137.8, 147.2, 149.61, 164.2 ppm; HR-FAB
+
MS [M+H] calcd for C H Cl NO 686.1478, found 686.1450.
3
5
35
3
7
Isopropyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (21) was obtained as a clear
syrup from glycosyl donor 1 and freshly distilled isopropanol in 77% yield (α/β = 1/3.6).
1
Analytical data for 21: R
f
= 0.60 (ethyl acetate/toluene, 2/3, v/v); selected H NMR data for α-21:
), 3.95 (sep, 1H, CH(CH ), 4.04-4.08 (m, 2H, H-3, 5), 5.02 (d,
H, J = 10.5 Hz, ½ CH Ph), 7.99 (d, 1H, J = 7.8 Hz, Pico) ppm; selected H NMR data for β-21:
δ, 1.15-1.16 (m, 6H, CH(CH
3
)
2
3 2
)
2
1
1
2
δ, 1.21-1.22 (m, 6H, CH(CH ) ), 3.45 (dd, 1H, J = 8.9 Hz, H-2), 3.95 (sep, 1H, CH(CH3)2),
3
2
2,3
4
.49 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.55 (dd, 1H, J = 5.4 Hz, J6a,6b = 11.6 Hz, H-6a), 4.70 (d, 1H,
5,6a
2
2
2
J = 10.8 Hz, ½ CH Ph), 4.79 (d, 1H, J = 10.6 Hz, ½ CH Ph), 4.88 (d, 1H, J = 10.8 Hz, ½
CH Ph), 8.04 (d, 1H, J = 5.8 Hz, Pico) ppm; selected C NMR data for the sugar region of α/β-
2
2
1
3
2
2
9
1: δ, 64.6, 68.6, 69.4, 72.8, 72.9, 73.2, 74.9, 75.0, 75.2, 75.9, 77.7, 77.8, 80.0, 82.1, 82.2, 84.8,
+
4.7, 102.3 ppm; HR-FAB MS [M+Na] calcd for C H NNaO 597.2727, found 620.2625.
36
39
7
Cyclohexyl 2,3,4-Tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (22) was obtained as a
clear syrup from glycosyl donor 1 and cyclohexanol in 63% yield (α/β = 1/2.0). Analytical data
1
for 22: R
3,4 = 9.2 Hz, H-3), 4.12 (m, 1H, H-5), 8.01 (d, 1H, J = 7.7 Hz, Pico) ppm; selected H NMR data
for β-22: δ, 3.48 (dd, 1H, J2,3 = 8.5 Hz, H-2), 3.68-3.71 (m, 2H, H-3, 5), 4.54 (d, 1H, J1,2 = 7.8
f
= 0.45 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data for α-22: δ, 4.06 (dd, 1H,
1
J
2
2
2 2
Hz, H-1), 4.71 (d, 1H, J = 10.9 Hz, ½ CH Ph), 4.79 (d, 1H, J = 10.8 Hz, ½ CH Ph), 4.88 (d,

ACCEPTED MANUSCRIPT
2
13
1
H, J = 10.9 Hz, ½ CH
2
Ph), 8.05 (d, 1H, J = 7.6 Hz, Pico) ppm; selected C NMR data for the
sugar region of α/β-22: δ, 64.4, 64.6, 68.7, 72.7, 73.0, 74.9, 75.0, 75.2, 75.9, 77.8, 77.9, 78.4,
+
8
6
0.0, 82.1, 82.2, 84.8, 94.6, 102.1 ppm; HR-FAB MS [M+Na] calcd for C H NNaO
39 43 7
60.2937, found 660.2946.
t-Butyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (23) was obtained as a clear
syrup from glycosyl donor 1 and t-butanol in 78% yield (α/β = 1/1.1). Analytical data for 23: R =
f
2
2
1
0
2
5
2
.31 (ethyl acetate/hexane, 2/3, v/v); [α]D 70.1 (c = 0.96, CHCl ); selected H NMR data for α-
3
3: δ, 3.61 (dd, 1H, J = 9.5 Hz, H-4), 4.07 (dd, 1H, J = 9.3 Hz, H-3), 4.20-4.22 (m, 1H, H-5),
4
,5
3,4
1
.13 (d, 1H, J1,2 = 3.4 Hz, H-1), 8.01 (d, 1H, J = 7.8 Hz, Pico) ppm; selected H NMR data for β-
1
3
3: δ, 3.45 (dd, 1H, J2,3 = 8.5 Hz, H-2), 8.03 (d, 1H, J = 7.7 Hz, Pico) ppm; selected C NMR
data for the sugar region of α/β-23: δ, 64.6, 64.8, 68.3, 72.7, 73.1, 75.0, 75.8, 78.1 (× 2), 82.0,
+
8
6
2.3, 85.1, 91.3, 97.8 ppm; HR-FAB MS [M+Na] calcd for C37
34.2771.
7
H41NNaO 634.2781, found
1
-Adamantyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (24) was obtained as a
clear syrup from glycosyl donor 1 and 1-adamantanol in 56% yield (α/β = 1/10). Analytical data
1
for 24: R = 0.69 (ethyl acetate/toluene, 2/3, v/v); selected H NMR data for α-24: δ, 4.07 (dd,
f
1
7
1
=
H, J = 9.1 Hz, H-3), 4.24-4.27 (m, 1H, H-5), 5.24 (d, 1H, J = 3.6 Hz, H-1), 8.02 (d, 1H, J =
3,4 1,2
1
.8 Hz, Pico) ppm; selected H NMR data for β-24: δ, 3.45 (dd, 1H, J = 8.8 Hz, H-2), 3.51 (dd,
2
,3
2
H, J4,5 = 9.4 Hz, H-4), 3.69 (dd, 1H, J3,4 = 9.0 Hz, H-3), 3.69-3.73 (m, 1H, H-5), 4.60 (d, 1H, J
11.0 Hz, ½ CH Ph), 4.77 (d, 1H, J = 10.9 Hz, ½ CH Ph), 4.88 (d, 1H, J = 11.0 Hz, ½
2
2
2
2
2
2
CH Ph), 4.93 (d, 1H, J = 10.7 Hz, ½ CH Ph), 4.99 (d, 1H, J = 10.9 Hz, ½ CH Ph), 8.05 (d, 1H,
J = 7.8 Hz, Pico) ppm; selected C NMR data for α-24: δ, 64.8, 72.6, 74.9, 75.4, 75.9, 78.2,
2
2
2
1
3
+
8
2.2, 85.1, 96.2 ppm; HR-FAB MS [M+Na] calcd for C H NNaO 712.3250, found 712.3265.
43 47 7
Phenyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (25) was obtained as a clear
f
syrup from glycosyl donor 1 and phenol in 81% yield (α/β = 1/4.7). Analytical data for 25: R =
1
0
4
.36 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data for β-25: δ, 4.10-4.15 (m, 1H, H-5),
.27 (dd, 1H, J13,4 = 9.8 Hz, H-3), 5.45 (d, 1H, J1,2 = 2.8 Hz, H-1), 8.75 (d, 1H, J = 5.0 Hz, Pico)
3
ppm; selected C NMR data for the sugar region of α/β-25: δ, 64.4, 73.1, 75.1, 76.0, 77.3, 77.7,
2.0, 84.7, 95.0, 101.6 ppm; HR-FAB MS [M+Na] calcd for C39
54.2479.
+
8
6
7
H37NO Na 654.2467, found
p-Methoxyphenyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranoside (26) was obtained
as a clear oil from glycosyl donor 1 and p-methoxyphenol in 63% yield (α/β = 1/5.5). Analytical
1
data for 26: R = 0.24 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data for α-26: δ, 4.17 (m,
f
1
H, H-5), 4.25 (dd, 1H, J = 9.2 Hz, H-3), 5.34 (d, 1H, J = 3.4 Hz, H-1), 8.75 (d, 1H, J = 4.5
3,4 1,2
1
2
Hz, Pico) ppm; selected H NMR data for β-26: δ, 4.98 (d, 1H, J = 10.8 Hz, ½ CH Ph), 5.07 (d,
1
2
2
H, J = 10.8 Hz, ½ CH Ph), 7.82 (dd, 1H, J = 7.4 Hz, Pico), 8.03 (d, 1H, J = 7.8 Hz, Pico), 8.80
2
1
3
(d, 1H, J = 4.4 Hz, Pico) ppm; C NMR data for the anomeric region of α/β-26: δ, 95.9, 102.7
+
ppm; HR-FAB MS [M+Na] calcd for C H NO Na 684.2573, found 684.2576.
4
0
39
8
p-Nitrophenyl 2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-
clear syrup from glycosyl donor 1 and p-nitrophenol in 52% yield (α/β = 1/1.2). Analytical data
for 27: R = 0.30 (ethyl acetate/hexane, 2/3, v/v); selected H NMR data for α-27: δ, 3.76 (dd, 1H,
f
D
-glucopyranoside (27) was obtained as a
7
1

ACCEPTED MANUSCRIPT
J
1
5
2,3 = 9.4 Hz, H-2), 4.22 (dd, 1H, J3 1, 4 = 9.1 Hz, H-3), 5.40 (d, 1H, J1,2 = 3.6 Hz, H-1), 8.71 (d,
2
H, J = 7.3 Hz, Pico) ppm; selected H NMR data for β-27: δ, 4.43 (dd, 1H, J = 11.7 Hz, H-6a),
1
3
.07 (d, 1H, J1,2 = 10.6 Hz, H-1), 8.83 (d, 1H, J = 7.3 Hz, Pico) ppm; selected C NMR data for
the sugar region of α/β-27: δ, 63.8, 64.1, 70.2, 73.5, 75.2, 75.3, 76.0, 76.2, 77.3, 79.6, 79.6, 81.6,
+
8
6
2.0, 84.6, 94.9, 100.4, ppm; HR-FAB MS [M+Na] calcd for C H N NaO 699.2319, found
99.2287.
3
9
36
2
9
ASSOCIATED CONTENT
1
13
Supporting Information. Additional experimental details, H and C NMR spectra for all new
compounds have been supplied as the Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*
Alexei V. Demchenko. E-mail: demchenkoa@umsl.edu
Author Contributions
The manuscript was written through contributions of all authors. / All authors have given
approval to the final version of the manuscript.
Funding Sources
This work was supported by grants from the National Institute of General Medical Sciences
(GM120673) and the National Science Foundation (CHE-1800350).
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Highlights
•
•
•
The glycosylations of the HAD-capable glycosyl donor showed a great variation of the results
depending on the nature of glycosyl acceptors used
Primary acceptors, both carbohydrate and aliphatic alcohols afforded the glycosylation products
with complete β-selectivity.
Both steric and electronic factors may have a strong effect on the stereoselectivity of HAD
glycosylations for the synthesis of β-glucosides